Abstract: Two strategies are currently in place to control the HIV pandemic: (1) anti-retroviral treatment reduces HIV-associated morbidity and mortality by controlling viral replication in infected subjects, thus also reducing the risk of viral dissemination; and (2) a comprehensive prevention package, including HIV vaccines, microbicides and pre-exposure prophylaxis regimens is being tested and aims at preventing new infections. Substantial effort has been invested in continuously improving these strategies, but there are several limitations to their further enhancement, many of which are related to HIV's vast mutational capacity. Instead of further refining current efforts that are confined by the limitations of these two strategies, we propose to introduce a third strategy. Our aim is to directly preserve the viability of uninfected CD4 T cells but not activated, infected cells, thus maintaining a functional immune system and limiting viral replication. HIV infection causes the loss of nave CD4 T cells, which incapacitates the adaptive immune response and thus ultimately leads to AIDS, the inability to fight off infections and development of certain cancers. The vast majority of CD4 T cells die without actually being infected. We propose to rescue these nave bystander CD4 T cells by targeting T cell metabolism. We present a strategy that aims to exploit the metabolic differences of uninfected, resting CD4 T cells and infected, activated CD4 T cells to selectively save the former but not the latter. This strategy is based on controlling the activity of pro-apoptotic BH3 family and tumor necrosis factor (TNF) superfamily members to control CD4 T cell viability. We propose to dissect how various metabolic signals are integrated in primary human CD4 T cells to regulate these apoptotic effector molecules using the recently established system of optogenetics. We propose that our strategy has merit to serve as a stand-alone approach or could be used in conjunction with both existing strategies to control the HIV pandemic. Public Health Relevance: HIV has caused the death of more than 25 million people. Despite efforts to limit mortality and further spreading of the virus there were still 2.6 million new infections and 1.8 million deaths in 2009. We propose a new strategy to combat this pandemic by manipulating T cell metabolism to prevent CD4 T cell loss and maintain a functional immune system with the goal of eliminating viral replication.